Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disease. HLRCC patients are at high risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations of the fumarate hydratase (FH) gene, which inactivates the enzyme and leads to elevated intracellular fumarate levels. In this project, we seek to identify activators of FH by quantitative high-throughput screening of in-house small molecule libraries. A robust resorufin-based fluorescent assay was developed and 57,037 small molecules were screened. Following confirmation in secondary assays and expansion of hit scaffolds through SAR exploration, a series of activators was identified. These compounds did not show redox activity in an Amplex red counterscreen, and the top molecules were confirmed to engage FH as measured via thermophoresis. Top compounds are currently undergoing advanced characterization of their activity for further development.